Impact of delayed systemic heparinization on postoperative bleeding and thromboembolism during post-cardiotomy extracorporeal membrane oxygenation in neonates.
von Stumm Maria,Subbotina Irina,Biermann Daniel,Gottschalk Urda,Mueller Goetz,Kozlik-Feldmann Rainer,Reichenspurner Hermann,Riso Arlindo,Sachweh Joerg S
Perfusion
INTRODUCTION:Veno-arterial extracorporeal membrane oxygenation is well-established for pediatric patients with post-cardiotomy heart failure. However, extracorporeal membrane oxygenation support is associated with major complications, that is, hemorrhage and thromboembolism. We seek to report our experience with delayed systemic heparinization during neonatal cardiac extracorporeal membrane oxygenation and its impact on bleeding and thromboembolism. METHODS:We retrospectively identified 15 consecutive neonates who were placed on extracorporeal membrane oxygenation after congenital heart surgery during a period of 3 years (2015-2017). Our anticoagulation protocol consisted of full heparin reversal by protamine after switching from cardiopulmonary bypass to extracorporeal membrane oxygenation (target activated clotting time: 120 ± 20 seconds). Administration of systemic heparinization was delayed until postoperative drainage volume declined to <1 mL/kg/h. Primary study endpoints were thromboembolism, bleeding, and requirement of blood products on extracorporeal membrane oxygenation. RESULTS:Our cohort (mean age: 13 ± 2.6 days; mean weight: 3.1 ± 0.3 kg; 66.7% male) required post-cardiotomy extracorporeal membrane oxygenation with a mean support time of 4.5 ± 2.2 days. Systemic heparinization was delayed averagely for 18.1 ± 9.3 hours. No thromboembolic events were observed on extracorporeal membrane oxygenation or after weaning. Relevant surgical site bleeding occurred in two patients (13.3%) requiring re-thoracotomy on the first postoperative day. Analysis of transfusion volumes revealed 24.5 ± 21.9 mL/kg/d mean packed red blood cells, 9.6 ± 7.1 mL/kg/d mean fresh frozen plasma, and 7.5 ± 5.7 mL/kg/d mean platelets. In-hospital survival was 86.6% (n = 13). CONCLUSION:In this retrospective analysis, the results of delayed systemic heparinization in neonatal post-cardiotomy extracorporeal membrane oxygenation could lead one to conclude that this routine is safe and favorable with low risk for thromboembolic events, reduced postoperative hemorrhage, and reduced blood product utilization.
10.1177/0267659120906046
Cangrelor PK/PD analysis in post-operative neonatal cardiac patients at risk for thrombosis.
Journal of thrombosis and haemostasis : JTH
Essentials An optimal therapeutic strategy has yet to be established to prevent early shunt thrombosis. A phase 1 study of cangrelor was performed in neonates after palliation of congenital heart disease. PD endpoint of >90% platelet inhibition in 60% of patients was achieved at 0.5 µg/kg/min dosing. No serious adverse events related to drug administration were observed, including bleeding. ABSTRACT: Background Systemic-to-pulmonary artery shunt thrombosis is a significant cause of early postoperative mortality in neonates after palliation of congenital heart disease. In the context of thromboprophylaxis, an optimal therapeutic strategy has yet to be established before aspirin administration. Cangrelor, a fast-acting, reversible P2Y inhibitor, may fill this unmet need. Objectives To evaluate the pharmacokinetics (PK), pharmacodynamics (PD), and safety of cangrelor in neonates undergoing stage 1 palliation. Methods This prospective, open-label, single-arm study evaluated two cangrelor dosing cohorts following placement of a systemic-to-pulmonary artery shunt, right ventricle-to-pulmonary artery shunt, or ductal stent. Drug concentrations and platelet reactivity, assessed by light transmission aggregometry and in microfluidic assays (MF), were measured. Results Twenty-two patients were consented and 15 received a 1-hour infusion of cangrelor at either 0.5 µg/kg/min (cohort 1) or 0.25 µg/kg/min (cohort 2). Whereas the primary PD endpoint was achieved at the higher dose (ie, reduction in maximal platelet aggregation by ≥90% in 60% of participants), only 29% of those in cohort 2 attained this goal. Comparable and statistically significant results were obtained in MF assays (P < .0001 vs. baseline). Drug levels during infusion were 3-fold higher in cohort 1 vs. cohort 2 (P < .001). Most participants (70%) had undetectable drug levels by 10 minutes postinfusion with full recovery in platelet function at 1 hour. No drug-related bleeding events occurred. Conclusions Favorable PK/PD properties of cangrelor 0.5 µg/kg/min dosing and safety profile warrant further evaluation in neonates following palliative cardiac procedures.
10.1111/jth.15141
Long-term outcomes of warfarin versus aspirin after Fontan surgery.
Attard Chantal,Monagle Paul T,d'Udekem Yves,Mackay Mark T,Briody Julie,Cordina Rachael,Hassan Ebrahim Bani,Simm Peter,Rice Kathryn,Ignjatovic Vera,
The Journal of thoracic and cardiovascular surgery
OBJECTIVES:Because of the nature of the Fontan physiology, patients are at an increased risk of thromboembolic complications. As such, warfarin or aspirin is generally prescribed lifelong for thromboprophylaxis. This study aimed to compare long-term rates of cerebrovascular injury, thrombosis, bleeding, bone mineral density, and quality of life in people living with Fontan circulation receiving warfarin compared with aspirin. METHODS:This was a multicenter study of a selected cohort from the Australia and New Zealand Fontan population. Participants underwent cerebral magnetic resonance imaging to detect the presence of cerebrovascular injury (n = 84) and dual-energy X-ray absorptiometry to assess bone mineral density (n = 120). Bleeding (n = 100) and quality of life (n = 90) were assessed using validated questionnaires: Warfarin and Aspirin Bleeding assessment tool and Pediatric Quality of Life Inventory, respectively. RESULTS:Stroke was detected in 33 participants (39%), with only 7 (6%) being clinically symptomatic. There was no association between stroke and Fontan type or thromboprophylaxis type. Microhemorrhage and white matter injury were detected in most participants (96% and 86%, respectively), regardless of thromboprophylaxis type. Bleeding rates were high in both groups; however, bleeding was more frequent in the warfarin group. Bone mineral density was reduced in our cohort compared with the general population; however, this was further attenuated in the warfarin group. Quality of life was similar between the warfarin and aspirin groups. Home international normalized ratio monitoring was associated with better quality of life scores in the warfarin group. CONCLUSIONS:Cerebrovascular injury is a frequent occurrence in the Australia and New Zealand Fontan population regardless of thromboprophylaxis type. No benefit of long-term warfarin prophylaxis could be demonstrated over aspirin; however, consideration must be given to important clinical features such as cardiac function and lung function. Furthermore, the association of reduced bone health in children receiving warfarin warrants further mechanistic studies.
10.1016/j.jtcvs.2020.12.102
High-dose heparin is associated with higher bleeding and thrombosis rates in pediatric patients following cardiac surgery.
Vorisek Carina N,Sleeper Lynn A,Piekarski Breanna,Lu Minmin,Rogers Jenna,Oladunjoye Olubunmi O,Emani Sitaram M
The Journal of thoracic and cardiovascular surgery
OBJECTIVE:To determine the association between unfractionated heparin (UFH) dose and the rate of postoperative bleeding and thrombosis events in pediatric cardiac patients. We tested the hypothesis that high-dose UFH is associated with higher rates of bleeding and thrombosis. METHODS:This is a retrospective review of pediatric patients admitted to the cardiac intensive care unit following cardiac surgery between November 2016 and December 2017. Peripheral venous thrombosis was excluded from analysis. Bleeding was defined as spontaneous bleeding remote from procedural manipulation. Postoperative UFH dosing strategy was categorized into 3 groups: no UFH, low-dose UFH (<15 U/kg/h) and high-dose UFH (≥15 U/kg/h). Statistical analysis was performed using multivariable logistic regression. RESULTS:We observed 966 consecutive patients (median age, 1.37 years; interquartile range, 0.27-5.50 years) during their stay in the cardiac intensive care unit. There were 94 patients (10%) with bleeding and 52 patients (5%) with thrombosis during follow-up. Patients receiving high-dose UFH experienced significantly more bleeding (odds ratio, 2.35; 95% confidence interval, 1.45-3.95) and thrombosis events (odds ratio, 3.65; 95% confidence interval, 1.81-7.38) compared with patients receiving low-dose UFH. The odds of bleeding (odds ratio, 0.81; 95% confidence interval, 0.45-1.47) and thrombosis (odds ratio, 0.59; 95% confidence interval, 0.26-1.35) were similar in the low-dose UFH and no-UFH groups. CONCLUSIONS:Bleeding remote from immediate postsurgical bleeding occurs uncommonly in pediatric patients following cardiac surgery. Anticoagulation with high-dose UFH is associated with higher bleeding rates as well as higher thrombosis rates. Indications for high-dose UFH should be carefully considered to reduce the rate of bleeding in this population.
10.1016/j.jtcvs.2019.06.015
Double-Blind, Randomized, Placebo-Controlled Trial Comparing the Effects of Antithrombin Versus Placebo on the Coagulation System in Infants with Low Antithrombin Undergoing Congenital Cardiac Surgery.
Jooste Edmund H,Scholl Rebecca,Wu Yi-Hung,Jaquiss Robert D B,Lodge Andrew J,Ames Warwick A,Homi H Mayumi,Machovec Kelly A,Greene Nathaniel H,Donahue Brian S,Shah Nirmish,Benkwitz Claudia
Journal of cardiothoracic and vascular anesthesia
OBJECTIVES:To determine whether precardiopulmonary bypass (CPB) normalization of antithrombin levels in infants to 100% improves heparin sensitivity and anticoagulation during CPB and has beneficial effects into the postoperative period. DESIGN:Randomized, double-blinded, placebo-controlled prospective study. SETTING:Multicenter study performed in 2 academic hospitals. PARTICIPANTS:The study comprised 40 infants younger than 7 months with preoperative antithrombin levels <70% undergoing CPB surgery. INTERVENTIONS:Antithrombin levels were increased with exogenous antithrombin to 100% functional level intraoperatively before surgical incision. MEASUREMENTS AND MAIN RESULTS:Demographics, clinical variables, and blood samples were collected up to postoperative day 4. Higher first post-heparin activated clotting times (sec) were observed in the antithrombin group despite similar initial heparin dosing. There was an increase in heparin sensitivity in the antithrombin group. There was significantly lower 24-hour chest tube output (mL/kg) in the antithrombin group and lower overall blood product unit exposures in the antithrombin group as a whole. Functional antithrombin levels (%) were significantly higher in the treatment group versus placebo group until postoperative day 2. D-dimer was significantly lower in the antithrombin group than in the placebo group on postoperative day 4. CONCLUSION:Supplementation of antithrombin in infants with low antithrombin levels improves heparin sensitivity and anticoagulation during CPB without increased rates of bleeding or adverse events. Beneficial effects may be seen into the postoperative period, reflected by significantly less postoperative bleeding and exposure to blood products and reduced generation of D-dimers.
10.1053/j.jvca.2018.05.052
Personalised Warfarin Dosing in Children Post-cardiac Surgery.
Al-Metwali Basma Zuheir,Rivers Peter,Goodyer Larry,O'Hare Linda,Young Sanfui,Mulla Hussain
Pediatric cardiology
Warfarin dosing is challenging due to a multitude of factors affecting its pharmacokinetics (PK) and pharmacodynamics (PD). A novel personalised dosing algorithm predicated on a warfarin PK/PD model and incorporating CYP2C9 and VKORC1 genotype information has been developed for children. The present prospective, observational study aimed to compare the model with conventional weight-based dosing. The study involved two groups of children post-cardiac surgery: Group 1 were warfarin naïve, in whom loading and maintenance doses were estimated using the model over a 6-month duration and compared to historical case-matched controls. Group 2 were already established on maintenance therapy and randomised into a crossover study comparing the model with conventional maintenance dosing, over a 12-month period. Five patients enrolled in Group 1. Compared to the control group, the median time to achieve the first therapeutic INR was longer (5 vs. 2 days), to stable anticoagulation was shorter (29.0 vs. 96.5 days), to over-anticoagulation was longer (15.0 vs. 4.0 days). In addition, median percentage of INRs within the target range (%ITR) and percentage of time in therapeutic range (%TTR) was higher; 70% versus 47.4% and 83.4% versus 62.3%, respectively. Group 2 included 26 patients. No significant differences in INR control were found between model and conventional dosing phases; mean %ITR was 68.82% versus 67.9% (p = 0.84) and mean %TTR was 85.47% versus 80.2% (p = 0.09), respectively. The results suggest model-based dosing can improve anticoagulation control, particularly when initiating and stabilising warfarin dosing. Larger studies are needed to confirm these findings.
10.1007/s00246-019-02215-y